Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([CH3:11])=[CH:4][CH2:5][O:6][CH2:7][CH:8](C)C.[CH2:12]1[O:20][C:19]2[CH:18]=[CH:17][C:16]([OH:21])=[CH:15][C:14]=2[O:13]1.[OH-].[K+].[CH3:24]OCCOC>>[CH:7]([O:6][CH2:5][CH:4]=[C:3]([CH3:2])[CH2:11][O:21][C:16]1[CH:17]=[CH:18][C:19]2[O:20][CH2:12][O:13][C:14]=2[CH:15]=1)([CH3:8])[CH3:24]
Reactant: Oc1ccc2c(c1)OCO2
Reactant: COCCOC
Reactant: CC(=CCOCC(C)C)CBr
Agent: [K+]
Agent: [OH-]
Product: CC(=CCOC(C)C)COc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.21 g (0.01 mol) of 1-bromo-4-isobutoxy-2-methyl-2-butene are added at 0° during the course of 5 minutes to 1.38 g (0.01 mol) of 3,4-methylendioxy-phenol and 0.56 g (0.01 mol) of potassium hydroxide in 40 cc of 1,2-dimethoxyethane. After stirring the reaction mixture at room temperature for 24 hours it is filtered and the solvent is distilled off at reduced pressure. The residue is dissolved in ether, washed with saturated salt solution, dried with sodium sulphate and evaporated. The residue is purified by chromatography on silica gel with hexane/ethyl acetate 9 : 1. 5-(4-isopropoxy-2-methyl-2-butenyloxy)-1,3-benzodioxol is obtained as colourless oil. nD20 = 1.5150.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH3:21])[C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:17])[NH2:16])=[O:8])(=O)C>O.N>[SH:4][CH2:5][CH:6]([CH3:21])[C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:16])[NH2:17])=[O:8]
Reactant: CC(=O)SCC(C)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Agent: N
Solvent: O
Product: CC(CS)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O

Procedure:
Nα -(3-Acetylthio-2-methylpropanoyl)-L-arginine (1 g.) is dissolved in a mixture of water (5 ml.) and concentrated ammonia (5 ml.). After one hour at room temperature the solution is concentrated to 3 ml. in vacuo (no heat) and ion exchange resin AG-50 W is added until the pH of approximately 4. The suspension is applied to a column of the same resin and the Nα (3-mercapto-2-methylpropanoyl)-L-arginine is eluted with pyridine-acetate buffer pH 6.5. The solvent is removed in vacuo and the residue is freeze dried, yield 0.86 g., m.p. 100°.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([O:15][C:16]1[C:21]([C:22]#N)=[CH:20][C:19]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[C:18]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[N:17]=1)[CH2:12][CH2:13][CH3:14].[OH2:41]>C1(C)C=CC=CC=1.CO>[CH2:11]([O:15][C:16]1[C:21]([CH:22]=[O:41])=[CH:20][C:19]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][CH:25]=2)=[C:18]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[N:17]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCOc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)cc1C#N
Reactant: O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Product: CCCCOc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)cc1C=O
Temperature: 25 °C

Procedure:
Diisobutyl aluminum hydride (1.0M in toluene, 3 mL, 3 mMol) was added in three portions over 26 hours (0 hrs., 24 hrs., 26 hrs.) to a solution of 2-butoxy-6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyridine-3-carbonitrile, Example 14, (0.42 gm, 1 mMol) in toluene (75 mL) and stirred at room temperature. Methyl alcohol (5 mL) was added dropwise followed by a solution of water (5 mL) in methyl alcohol (25 mL). The layers were separated and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to a semi-solid. The products were separated and purified by silica gel chromatography. Example 29 Anal. Calc. C23 H24NO4SF: C, 64.32; H, 5.63; N, 3.26. Found: C, 64.27; H, 5.59; N, 3.23. Example 30 Anal. Calc. C23H22NO4SF: C, 64.62; H, 5.19; N, 3.28. Found: C, 64.84; H, 5.39; N, 3.58.
Reaction SMILES: [C:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])(=[O:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[C:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][C:17](=[O:19])[CH3:18])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccccc1N
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(=O)Nc1ccccc1C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-acetylaniline (1 ml; 8.3 mmol) and acetic anhydride (10 ml) was stirred overnight at ambient temperature. Saturated aqueous sodium carbonate was added till basic reaction and the resulting mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulphate and evaporated under reduced pressure to leave N-(2-acetylphenyl)acetamide quantitatively. This product was dissolved in ethanol (40 ml) and hydroxylamine, hydrochloride (0.94 g; 13.6 mmol) was added. The mixture was heated to reflux for 7 hours and then left at ambient temperature overnight. The solvent was removed by evaporation and the residue was partitioned between ethyl acetate and aqueous sodium carbonate. The organic phase was concentrated and subjected to chromatography on silica gel using a mixture of ethyl acetate and methanol (9:1 v/v) as the eluent. Yield: 0.26 g (15%). Mp. 99-100° C.
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:13])[NH:7][C:6](=[O:8])[C:5]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:4]12.[C:14]([O:18][C:19](=[O:33])[C@H:20]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH2:22][CH2:23]I)([CH3:17])([CH3:16])[CH3:15]>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[C:14]([O:18][C:19](=[O:33])[C@H:20]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH2:22][CH2:23][N:7]1[C:3](=[O:13])[C:4]2[C:5](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6]1=[O:8])([CH3:15])([CH3:16])[CH3:17]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H](CCCI)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CCCN1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 99.9 %

Procedure:
Sodium hydride (0.522 g, 13.05 mmol) is added to a solution of phthalimide (2.33 g, 15.84 mmol) and 18-crown-6 (0.01 g) in 20 mL of N,N-dimethylformamide (DMF). After stirring at RT for 20 min, a solution of the title F compound, (2R)-(t-butyloxycarbonylamino)-5-iodopentanoic acid t-butyl ester (4.61 g, 11.55 mmol) in 5 mL of DMF is added, and the solution is stirred at RT for 30 min, then at 60° C. for 8 h. The solvent is removed under reduced pressure, and the residue is partitioned between 300 mL of ethyl acetate and 225 mL of 0.05M aqueous HCl. The organic phase is washed with 100 mL water and 50 mL of brine, dried over anhydrous Na2SO4 and concentrated to give 4.83 g (100%) of (2R)-(t-butyloxycarbonylamino)-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid t-butyl ester as a tan solid: NMR(CDCl3) 1.43 (s, 9H), 1.45 (s, 9H), 1.60-1.88 (m, 4H), 3.71 (t, 2H, J=6.6), 4.18-4.26 (m, 1H), 5.06 (br d, 1H, J=7.9), 7.70-7.73 (m, 2H), 7.83-7.86 (m, 2H); IR 1712, 1500, 1155; ESI-MS 290 (M++1).
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22]CC)=[O:21])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[C:25]1[CH:34]=[CH:33][C:32]2[C:31]([CH3:36])([CH3:35])[CH2:30][CH2:29][C:28]([CH3:38])([CH3:37])[C:27]=2[CH:26]=1.Cl>O1CCCC1>[OH:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([OH:22])=[O:21])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[C:25]1[CH:34]=[CH:33][C:32]2[C:31]([CH3:36])([CH3:35])[CH2:30][CH2:29][C:28]([CH3:38])([CH3:37])[C:27]=2[CH:26]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCO)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(-c3cc(-c4ccc(C(=O)O)cc4)ccc3OCCCO)ccc21
Temperature: 40 °C
Reaction time: 48 h
Yield: 90.4 %

Procedure:
2.05 ml (2.05 mmol) of an aqueous solution of sodium hydroxide (1 M) are added to a solution of 0.20 g (0.41 mmol) of ethyl 4′-(3-hydroxypropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylate in 5 ml of tetrahydrofuran. The reaction mixture is stirred for 48 h while heating at 40° C. The reaction mixture is placed under a stream of nitrogen in order to eliminate the tetrahydrofuran and then 2.5 ml (2.5 mmol) of a solution of hydrochloric acid (1 M) are added. The product precipitates in the form of a white solid. After filtration, the product is washed twice with 5 ml of diethyl ether and then placed in an oven under vacuum overnight. 0.17 g of 4′-(3-hydroxypropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylic acid is obtained (white solid, Mp=317° C., yield=90%).
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].[OH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]=O)=[CH:11][CH:10]=1.[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO.CCOC(C)=O>[CH2:15]([C:12]1[CH:13]=[CH:14][C:9]([CH2:8][OH:7])=[CH:10][CH:11]=1)[CH2:16][C:17]#[CH:1]
Reactant: O=C([O-])[O-]
Reactant: O=CCCc1ccc(CO)cc1
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#CCCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
8.5 g (61.5 mmol) K2CO3 are added to a solution of 5.0 g (30.4 mmol) 3-(4-hydroxymethyl-phenyl)-propionaldehyde in 100 mL MeOH and then a solution of 7.0 g (36.4 mmol) dimethyl (1-diazo-2-oxo-propyl)-phosphonate in 50 mL MeOH is added dropwise and stirred for 3 h at RT. The reaction mixture is diluted with 200 mL EtOAc, washed with 80 mL saturated NaHCO3 solution, the aqueous phase extracted with 100 mL EtOAc and the combined organic phases are dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography on silica gel (cyc/EtOAc 3:1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[C@H:4]([CH2:6][SH:7])[NH2:5].[CH:9]([CH2:11][CH2:12][CH2:13][C@H:14]([N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])[C:15]([OH:17])=[O:16])=O>O1CCCC1.C(Cl)(Cl)Cl>[C:15]([CH:14]([N:18]1[C:19](=[O:28])[C:20]2=[CH:27][CH:26]=[CH:25][CH:24]=[C:21]2[C:22]1=[O:23])[CH2:13][CH2:12][CH2:11][CH:9]1[NH:5][C@H:4]([C:3]([O:2][CH3:1])=[O:8])[CH2:6][S:7]1)([OH:17])=[O:16]
Reactant: COC(=O)[C@@H](N)CS
Reactant: O=CCCC[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H]1CSC(CCCC(C(=O)O)N2C(=O)c3ccccc3C2=O)N1

Procedure:
A solution of L-cysteine methyl ester (1.71 g) and 5-formyl-2(S)-phthalimidopentanoic acid (3.49 g) in 120 ml of tetrahydrofuran was stirred under nitrogen for 2.5 hours and then taken to dryness to yield a white foam. This residue was dissolved in 250 ml of chloroform and washed with water (2×30 ml). The combined aqueous layers were back extracted with chloroform (2×30 ml). The organic layers were dried (Na2SO4) and then concentrated in vacuo to give a white foam, 4.83 g. Tlc on silica [4:1 Ethyl acetate:acetic acid] indicated a major spot at Rf =0.72. Exact mass measurement showed a molecular ion at 392.1024 (calcd. 392.1041). 'H NMR spectrum (CDCl3) showed a multiplet at δ7.72 (4H) and a singlet at δ3.78(3H).
Reaction SMILES: [CH2:1]([C:3]1[N:7]=[C:6]([CH:8]([CH3:12])[C:9]([OH:11])=O)[O:5][N:4]=1)[CH3:2].[CH2:13]([N:16]=C=O)[CH2:14][CH3:15].COC1C=C[N+]([O-])=CC=1.O>C1(C)C=CC=CC=1.C(N1C=CN=C1)=C>[CH2:13]([NH:16][C:9](=[O:11])[CH:8]([C:6]1[O:5][N:4]=[C:3]([CH2:1][CH3:2])[N:7]=1)[CH3:12])[CH2:14][CH3:15]
Reactant: CCCN=C=O
Reactant: CCc1noc(C(C)C(=O)O)n1
Agent: C=Cn1ccnc1
Agent: COc1cc[n+]([O-])cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCNC(=O)C(C)c1nc(CC)no1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 47.3 %

Procedure:
Employing anhydrous conditions, 17 mmol of about 90% pure α-(3-ethyl-1,2,4-oxadiazol-5-yl)-propionic acid (=3 ethyl-α-methyl-1,2,4-oxadiazol-5-yl-acetic acid) were dissolved in 40 ml of toluene and about 20.5 mmol of n-propyl-isocyanate and about 60 mg of the catalyst (a saturated solution of 4-methoxy-pyridine-1-oxide.1 H2O in N-vinyl-imidazole) were added to the solution. While a slow stream of nitrogen was continuously passed over the surface, the reaction mixture was stirred for 5.5 hours at room temperature and the reaction mixture was evaporated in vacuo. The residue was dissolved in 100 ml of a 1:1 mixture of ethyl acetate and diethyl ether and this solution was extracted 4 times at pH 2.0 with 10 ml of water. The combined acid washings were extracted once with 10 ml of ethyl acetate and discarded. The two organic layers were combined and extracted 3 times at pH 7.0 with 10 ml of water. The combined washings were extracted once with 10 ml of ethyl acetate and discarded. The combined organic layers were treated with activated carbon, dried over anhydrous magnesium sulfate, filtered and completely evaporated in vacuo. The residue was stirred in 20 ml of n-hexane, whereupon diethyl ether was added slowly till the solid was almost completely dissolved. After filtration, the solution was gradually cooled to -18° C. and the crystalline precipitate was collected by filtration, washed repeatedly with n-hexane and with very cold diethyl ether to obtain 1.7 g (about 50% yield) of N-propyl-α-(3-ethyl-1,2,4-oxadiazol-5-yl)-propionamide with a purity of about 95% (according to TLC and PMR spectrum) and a m.p. of 52°-53° C.
Reaction SMILES: [CH:1]([CH:3]([OH:26])[C@H:4]1[O:8][C@@H:7]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:6][C@@H:5]1[O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH2:2].Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29].N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C>[C:28]([O:26][CH:3]([CH:1]=[CH2:2])[C@H:4]1[O:8][C@@H:7]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:6][C@@H:5]1[O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:21])([O:30][CH2:31][CH3:32])=[O:29]
Reactant: C=CC(O)[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CCOC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CC(OC(=O)OCC)[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of 5'-vinyl-3'-O-t-butyldimethylsilyl thymidine (2.0 g) in 30 ml of methylene chloride was added ethyl chloroformate (6 eq.) and pyridine (12 eq.) and the resulting mixture was stirred for 2 hours. The mixture was diluted with ethyl acetate, washed with aqueous sodium bicarbonate, then with water (2×25 ml), and then with brine. Then the organic layer was dried. The title compound was purified by flash chromatography using 20% ethyl acetate/hexane.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-:22].[Cl-].[Cl-].[Cl:25][CH2:26][CH2:27][C:28](Cl)=[O:29].Cl>[N+](C1C=CC=CC=1)([O-])=O>[ClH:25].[CH2:17]([N:16]([CH2:19][CH3:20])[CH2:15][CH2:14][N:12]1[C:11]2[CH:10]=[CH:9][C:8]([C:28](=[O:29])[CH2:27][CH2:26][Cl:25])=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[C:3]([C:28](=[O:29])[CH2:27][CH2:26][Cl:22])[CH:4]=2)[CH3:18]
Reactant: CCN(CC)CCn1c2ccccc2c2ccccc21
Reactant: [Cl-]
Reactant: O=C(Cl)CCCl
Agent: Cl
Agent: [Al+3]
Solvent: O=[N+]([O-])c1ccccc1
Product: CCN(CC)CCn1c2ccc(C(=O)CCCl)cc2c2cc(C(=O)CCCl)ccc21
Reaction time: 0.67 h
Yield: 70.3 %

Procedure:
A solution of compound 32 (17.9 g, 67.3 mmol) in nitrobenzene (150 mL) was cooled in an ice bath. AlCl3 (45.0 g, 337.1 mmol) was added in portions. Then 3-chloropropionyl chloride (32.4 mL, 336.7 mmol) was added dropwise for 10 min. The reaction mixture was stirred for 40 min (LC/MS monitoring), poured into a mixture of ice with diluted HCl, and extracted with CHCl3. The extract was evaporated. The residue was purified by chromatography in a thick short column (silica gel, CHCl3/MeOH 99:1→90:10) to afford 22.9 g (76.3%) of the hydrochloride 33.
Reaction SMILES: IC.[C:3]([O-:6])([O-])=O.[K+].[K+].[CH2:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[C:13]=1O)[CH:10]=[CH2:11]>CC(C)=O.O>[CH2:9]([C:12]1[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[C:17]=1[O:6][CH3:3])[CH:10]=[CH2:11]
Reactant: O=C([O-])[O-]
Reactant: C=CCc1cc(F)cc(F)c1O
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CC(C)=O
Product: C=CCc1cc(F)cc(F)c1OC
Yield: 61.7 %

Procedure:
A solution of iodomethane (1.8 mL, 29.4 mmol), K2CO3 (2.4 grams, 17.6 mmol) and 2-Allyl-4,6-difluorophenol (1.0 grams, 5.9 mmol) in 20 mL acetone was refluxed overnight. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated. Flash chromatography (Hexane) afforded 0.67 g (63%) of the title compound. 1H NMR (400 MHz, CDCl3). S 3.36 (d, 21), 3.82 (s, 3H), 4.97-5.12 (m, 2H), 5.85-6.0 (m, 1H), 6.4-6.5 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=[N:13][C:14]=1[CH2:15][CH3:16].BrC1N=C(CC)C(N[CH:40]2[C:49]3[C:44](=[CH:45][C:46]([O:50][CH3:51])=[CH:47][CH:48]=3)[CH2:43][CH2:42][CH2:41]2)=NC=1CC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][CH:40]2[C:49]3[C:44](=[CH:45][C:46]([O:50][CH3:51])=[CH:47][CH:48]=3)[CH2:43][CH2:42][CH2:41]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(NC2CCCc3cc(OC)ccc32)c(CC)nc1Br
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1NC1CCCc2cc(OC)ccc21

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-3,6-diethyl-N-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine, ethylene glycol dimethyl ether and tetrakis(triphenylphosphine) palladium and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 7.51, 7.31, 6.81, 6.71, 5.44, 4.63, 3.83, 2.93–2.76, 2.66–2.51, 2.10, 1.91, 1.32–1.14; HRMS (FAB) calcd for C25H27Cl2N3O+H 456.1609, found 456.1624; Anal. Calcd for C25H27Cl2N3O: C, 65.79; H, 5.96; N, 9.21. Found: C, 65.58; H, 5.96; N, 8.99.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[N:3]=1.[NH:22]1[CH:26]=[N:25][C:24]([NH2:27])=[N:23]1>C(O)C>[NH:22]1[CH:26]=[N:25][C:24]([NH:27][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]([F:21])([F:20])[F:19])[N:3]=2)=[N:23]1
Reactant: Nc1nc[nH]n1
Reactant: FC(F)(F)c1ccccc1-c1cc2ccccc2c(Cl)n1
Solvent: CCO
Product: FC(F)(F)c1ccccc1-c1cc2ccccc2c(Nc2nc[nH]n2)n1
Temperature: 160 °C
Yield: 4 %

Procedure:
A solution of 1-chloro-3-(2-trifluoromethyl-phenyl)-isoquinoline (0.326 mmol) and 1H-[1,2,4]triazol-3-ylamine (0.651 mmol) in ethanol (3 mL) was heated at 160° C. and the solvent evaporated with a stream of nitrogen. The remaining oil was then heated at 160° C. for 18 hours under nitrogen. The resulting melt was dissolved in 5% methanol/dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate (1×25 mL) then dried over magnesium sulfate. Purification by silica gel chromatography afforded IX-175 as a colorless oil (4% yield). 1H NMR (500 MHz, CDCl3) δ 9.18 (d, 1H), 8.82 (s, 1H), 7.90 (d, 1H), 7.85-7.75 (m, 3H), 7.71-7.62 (m, 3H), 7.60-7.55 (m, 2H), 4.42-4.35 (m, 1H). LC-MS (ES+) 356.16 (M+H); HPLC-Method D, Rt 3.55 min.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[N:12]([Si](C(C)C)(C(C)C)C(C)C)[CH:11]=2)O)=[CH:6][CH:5]=[C:4]([NH:30][C:31]2[CH:32]=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[N:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.O>ClCCCl>[F:1][C:2]1[N:3]=[C:4]([NH:30][C:31]2[CH:32]=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[NH:12][CH:11]=1
Reactant: COc1ccc(Nc2ccc(C(O)c3cn([Si](C(C)C)(C(C)C)C(C)C)c4ncc(C)cc34)c(F)n2)cn1
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: COc1ccc(Nc2ccc(Cc3c[nH]c4ncc(C)cc34)c(F)n2)cn1
Temperature: 80 °C
Reaction time: 3 h
Yield: 70.4 %

Procedure:
To [2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridin-3-yl]-(5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (68, 0.220 g, 0.411 mmol) in 20.0 mL of 1,2-dichloroethane, triethylsilane (2.0 mL, 12 mmol) and trifluoroacetic acid (1.0 mL, 13 mmol) are added and the reaction stirred at 80° C. for 3 hours. The reaction is poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (P-3019, 105.1 mg). MS (ESI) [M+H+]+=364.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:4][N:3]=1.C(N(CC)CC)C.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(Cl)Cl>[CH3:15][C:10]1([CH3:16])[C:11]([CH3:14])([CH3:13])[O:12][B:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:24](=[O:26])[CH3:25])=[N:3][CH:4]=2)[O:9]1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (120 mg) in dry DCM (3 ml) and triethylamine (1.5 equiv., 114 uL) was added acetic anhydride (1.1 equiv., 57 ul) and the reaction mixture was stirred at room temperature overnight. Dichloromethane/brine extraction and purification on silica gave 66 mg of N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl]-acetamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Na+].I[CH2:25][CH3:26].O>CN(C)C=O.C(O)C>[CH2:25]([O:15][C:8]([C:6]1[CH:5]=[CH:4][C:3]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:2]([F:1])[CH:7]=1)([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:26]
Reactant: CCOC(=O)C(C)(O)c1ccc(-c2ccccc2)c(F)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(OCC)c1ccc(-c2ccccc2)c(F)c1
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, ethyl 2-(2-fluoro-biphenyl-4-yl)-2-hydroxy-propionate (Japanese Patent Unexamined Publication No. 52-105,144) (15.0 g) was dissolved in N,N-dimethylformamide (300 ml) and then sodium hydride (4.16 g, 60% oily) was added under ice-cooling, after which the resulting mixture was stirred for one hour. Subsequently, iodoethane (10.4 ml) was added and the resulting mixture was stirred for 12 hours. To the reaction mixture were added a small amount of water and ethanol, and thereafter, the solvent was removed by azeotropic distillation using toluene. To the residue was added ethyl acetate and the resulting mixture was neutralized with a saturated aqueous sodium bicarbonate solution and then subjected to extraction with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure to obtain ethyl 2-ethoxy2-(2-fluoro-biphenyl-4-yl)-propionate.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[CH3:21][S:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[S:22][CH3:21])[CH2:34][CH2:33]2)=[O:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: COc1nc(C)c(C)nc1NC(=O)Oc1ccccc1
Reactant: CSc1ccccc1N1CCNCC1
Product: COc1nc(C)c(C)nc1NC(=O)N1CCN(c2ccccc2SC)CC1
Yield: 71 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)carbamate and 1-(2-methylthiophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.